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Epic Genetics
By Tina Hesman Saey
May 9th, 2008

Genes’ chemical clothes may underlie the biology behind mental illness

In research circles the debate is settled. Psychiatric illnesses are disorders rooted in biology.

As convincing as the evidence is, mysteries still fog our understanding of mental illnesses. Yes, the disorders stem from problems in the brain, but “on the other hand, for time and ages people have been looking at brains under the microscope, and they don’t see much,” says Schahram Akbarian, a psychiatrist and neuroscientist at the University of Massachusetts Medical School in Worcester. No lesions, malformations, scars or other outward signs distinguish a mentally ill brain from a healthy one.

In recent years, researchers have searched the genome for mutations linked to mental illness. The scans have been fruitful, perhaps too fruitful. Hundreds of genes have been implicated in predisposing a person to such disorders as addiction, schizophrenia, bipolar disorder, depression or anxiety. But no gene has been shown to be a master switch.

The debate has raged for decades over whether mental illnesses sprout from nature or nurture. Scientists now suspect both. A new field linking genes and environment may chart the way for solving some of the mysteries shrouding mental illness.

Genes alone can only explain a few of the reasons people contract mental illnesses, become addicts or have developmental disorders, such as autism. Identical twins share a genetic makeup, so if genes controlled psychiatric disorders, whenever one twin developed a mental illness, the other would too. But that’s not how it happens. Depending on the disorder, both twins develop it only about half the time. “We know the genetic risk of mental illness is about 50 percent, which leaves a whole other 50 percent unaccounted for,” says Eric J. Nestler of the University of Texas Southwestern Medical Center at Dallas.

Some people say nurture, that is, “environment,” is the root of psychiatric disorders, or at the very least accounts for the remainder of the risk. But no one has ever pinpointed exactly which experiences, infections, chemical exposures, types of stress or other environmental factors tip some brains into mental illness while others remain healthy despite the same insults, Akbarian says.

Scientists have also long sought explanations for why psychiatric disorders are so enduring, coming on slowly and then waxing and waning throughout life, or plunging addicts into craving, years after they’ve stopped taking drugs. Even the medications used to treat depression take weeks to grant relief.

The emerging field of epigenetics (which means “beyond genes”) lies at this interface between genetics and environment and is revealing what marketers and Hollywood types have known for ages — that packaging is important.

Epigenetics is elucidating how environmental cues make their marks on genes. Such discoveries could help in understanding the mentally ill mind and lead to new treatments for psychiatric disorders and addiction.

Changing and not forgetting
Epigenetic mechanisms alter how cells use genes but don’t change the DNA code in the genes themselves. The term “epigenetic” has been used for 60 years to describe the changes an organism experiences as it develops, but it has recently come to refer to the dozens of different modifications that DNA and its associated proteins undergo. All of the alterations essentially perform the same job: packaging genes properly.

Some of the modifications package genes so that they are shrink-wrapped tighter than a brand new CD, and just as hard to get into. Other epigenetic changes give cellular machinery easy access to genes. The ultimate effect is to finely tune to what degree a gene is turned on or off. Often the fine tuning is long-lasting, setting the level of a gene’s activity for the lifetime of the cell.

Such extra-genetic programming is essential for cells to establish and maintain their identities throughout life.

“We don’t need dopamine receptors in muscle cells, and we don’t need neurons that produce liver enzymes,” says Arturas Petronis, director of the Krembil Family Epigenetics Lab at the University of Toronto in Canada.

But the instructions for making dopamine receptors, liver enzymes, hair follicles and every structure in the body are found in every cell. Somehow unneeded genes must be shut down, and the genes that are necessary to form a particular cell type must be turned on. And once a cell’s fate is determined, the course must be maintained.

Genes “without the right regulation can’t perform all these functions,” Petronis says.

Enter epigenetics, the molecular equivalent of the permanent record.

Once cells are programmed to be a brain, liver or heart cell, “they remember how to be that cell for the rest of their lives,” says J. David Sweatt of the University of Alabama at Birmingham.

When cells “forget” their epigenetic programming, cancer or other diseases may result. But sometimes holding on to a program can be just as harmful, especially if that programming spurs a craving for cocaine or leads to obsessive hand washing or endless depression.

Programming errors
Scientists are only beginning to learn how psychiatric disorders are linked to the packaging of DNA and the genes it contains.

One of the best studied of the epigenetic packaging choices is DNA methylation. Cells chemically mark genes they want to turn off by tacking a methyl group (one carbon and three hydrogen atoms) to the DNA base cytosine. But not just any old cytosine (the C of the DNA alphabet) gets modified. The alteration happens primarily where the DNA sequence consists mostly of C’s and G’s (the DNA base guanine). Scientists call such sequences CpG islands.

Genes have control regions that work like light switches or thermostats to flip genes on or off or nudge the level of activity up or down. CpG islands are often found in or near these control regions.

When a methyl group is pasted onto a C, a sort of molecular police tape goes up, declaring a gene off-limits to proteins called transcription factors that turn genes on. Other proteins act as guards to make sure that no transcription factors sneak past the tape.

Petronis and colleagues examined DNA-methylation patterns in brain tissue from deceased people who had had schizophrenia or bipolar disorder and from deceased people who had been mentally healthy. The group surveyed more than 7,000 CpG islands and found that about one in every 200 was methylated differently in people with major psychosis — a collective term for schizophrenia and bipolar disorder — than in people free from those disorders. That means that many genes are regulated differently in people with schizophrenia and bipolar disorder.

Some of the alterations affect activity of genes that are involved in regulating the brain’s chemical communication system, its development or its response to stress. Some of the modifications even make tiny cellular powerhouses, called mitochondria, work differently.

Sperm from men with major psychosis also had altered DNA methylation compared with sperm from healthy men, the group reported in the March issue of the American Journal of Human Genetics. The result could mean that epigenetic packaging systems are faulty in people with schizophrenia and bipolar disorder.

“The good news is we have epigenetic changes,” Akbarian says. “The bad news is that they are not so dramatic to give the telltale sign of disease.”

Several subtle epigenetic changes may add up to psychiatric disease, especially when paired with DNA mutations that make brains vulnerable to stress, he says.

Of mice and people
DNA methylation is only one of dozens of various epigenetic packaging materials. Epigenetics is all about “–ylation,” that is, the addition of one kind of chemical group or another to various proteins, fats, DNA and other molecules. Adding an acetyl group to a protein, for instance, is called acetylation. Tacking on phosphorus is, yes, phosphorylation, and so on.

DNA and its associated proteins are known collectively as chromatin. The most intimate of those proteins — called histones — are popular targets for modification. To fit nearly six feet of DNA inside a microscopic nucleus, a cell has to pack more efficiently than a tourist on a trip around the world. Histones are handy space-saving devices. Eight histone proteins get together and form a core around which DNA is wrapped. Other proteins help fold the DNA-histone complex into ever tighter structures until it can nestle comfortably in the cell nucleus.

These packing proteins are multitaskers. While stuffing DNA inside the nucleus, the proteins also help determine which genes will be turned off and on. The various epigenetic chemical modifications help direct the packing process, effectively deciding whether certain genes will be relegated to the bottom of the suitcase or stowed in accessible side compartments.

Snapping acetyl groups onto the tails of some of the histone proteins, for example, helps loosen the connection between DNA and histones, making genes more accessible to transcription factors. Phosphorylation and methylation of histones may either turn genes off or on, depending on where the chemicals are pinned to the histone tail.

Nestler and his colleagues have found that dramatic changes in chromatin packaging around a gene are linked to depression and addiction. Activity levels of a gene called BDNF (for brain-derived neurotrophic factor) in mice that are bullied day after day fall to about one-third the level found in non-stressed mice. The chronic bullying causes mice to avoid social contact with other animals, a symptom of depression. The “chronic defeat stress” experienced by the mice might also be a model for post-traumatic stress disorder, anxiety disorders and social phobias.

And just as people don’t just snap out of depression, mice don’t easily get over bullying once they are allowed to lead a peaceful life. Their defeated demeanors persist for weeks after the bullying stops, as does the reduced activity of BDNF in their brains.

Antidepressants, such as imipramine and Prozac, reverse the effects of bullying on both social interactions and gene activity, but only when the mice keep taking the drug. A single dose of antidepressants doesn’t help, Nestler says.

That trend is similar to the way antidepressants work in people. The drugs typically take several weeks to change how people feel and usually must be taken long-term to maintain beneficial effects.

Nestler and his colleagues looked closely at what happens to chromatin around the switches that control BDNF levels. The researchers found stressed mice had much higher levels of histone methylation than non-stressed mice had. In this case, methylation helps to close off chromatin and adjusts the thermostat to turn down BDNF activity.

Imipramine restores gene activity in the stressed mice, but it doesn’t remove the repressive methylation from the histones. Instead, it doubles acetylation of one of the histones. Acetylation helps loosen chromatin, allowing cellular machinery better access to the genes. The antidepressant didn’t increase acetylation in unstressed mice, indicating that the modification only happens to genes that are already tattooed with methylation. The antidepressant may increase acetylation by inhibiting enzymes, called histone deacetylases, which would otherwise remove acetyl groups from histones.

In fact, the researchers found that bullied mice on imipramine made less of an enzyme called histone deacetylase 5 (HDAC5), but mice in the no-stress group had normal levels of HDAC5 even after taking the antidepressant. The finding is notable because antidepressants such as imipramine are generally thought to have no effect on healthy people but to lift the spirits of people with depression, the researchers said in a 2006 Nature Neuroscience article describing the study.

Sodium butyrate, a drug that inhibits the action of histone deacetylases, also works as an antidepressant in mice, Akbarian and his colleagues reported last year in Biological Psychiatry. The result suggests that chromatin-modifying drugs could be therapeutic for some psychiatric disorders either alone or in combination with other medications.

Addictive packaging
Epigenetic modifications may also account for some of the long-lasting effects of drug abuse.

When a person takes the first hit of cocaine, the brain’s reward system feels it right away. A region near the base of the brain called the ventral tegmental area releases a flood of the feel-good chemical dopamine to another brain structure known as the nucleus accumbens. Drugs of abuse cause the nucleus accumbens to get a shot of dopamine or similar reward chemicals.

The dopamine signal spurs production of a transcription factor known as CREB. CREB’s job is to turn on other genes, including one involved in stopping the flood of dopamine coming from the ventral tegmental area.

That stifling of the reward system breeds tolerance to drugs of abuse because the more CREB produced, the higher the dose of cocaine needed to overcome its dampening effects.

But the CREB gene switches off after only a few days without drugs. It can’t account for drug addiction’s staying power. Another gene, known as delta-FosB, also switches on when a wave of dopamine washes over the nucleus accumbens. Unlike short-lived CREB, the delta-FosB protein is a molecular Energizer Bunny. It persists for weeks after a dose of drugs.

Delta-FosB teams up with other transcription factors and recruits enzymes that acetylate histones and remodel control regions of some genes, such as Cdk5. The CDK5 protein then alters another protein that interacts with histone deacetylase enzymes, creating yet more chromatin renovations.

Such findings suggest that medicines that interrupt or reverse epigenetic changes (see sidebar) caused by drugs of abuse could one day prevent or cure addiction. The findings also shed light on the way the brain gets high on life. Activity of the gene for delta-FosB is “also induced by high doses or consumption of natural rewards,” such as exercise, sugar, high fat diets and sexual activity, Nestler said at a symposium on epigenetics and behavior held in March in Houston.

The way genes are packaged also influences learning and memory. Defects in DNA methylation are at the heart of Rett syndrome, an inherited form of autism that affects mostly girls. Other epigenetic changes have been linked to autism and to some types of mental retardation.

Long-lasting effects of epigenetic packaging may seem to consign some people to a lifetime of mental illness, but scientists studying the disorders take heart that the problems can be influenced by packaging. That means that even people who have battled depression or schizophrenia for years may one day be able to take a medication that would repackage their genes in a healthier manner.

People who are susceptible to psychiatric disorders or addiction might be able to effectively inoculate themselves against the disorders by taking a tonic to prevent their genes from getting wrapped up incorrectly. Such draughts are likely years or even decades away from showing up in the pharmacy, but scientists finally may be within yanking distance of the cloak of mystery covering mental illness.